Anti- Epileptic drugs

It is a collective term applied for a group of convulsive disorders

The common features of epilepsy are

Loss or disturbance of consciousnesses

Characteristic body movements (usually, but not always)

CLASSIFICATION

1. Hydantoins

Phenytoin

2. Barbiturates

Phenobarbitone

Primidone

3. Iminostilbbenes

Carbamazepine

4. Succinimides

Ethosuximided

5. Aliphatic carboxylic acid

Sodium valproate

6. Benzodiazepines

Clonazepam

Clobazam

Diazepam

7. Newer antiepileptic

Lamotrigine

Gbapentine

8. Miscellaneous

Trimethadione

Acetazolamide

Phenytoin

Phenytoin was synthesized in 1908, but its anticonvulsant property was discovered only in 1938

It is effective in suppressing tonic-clinic and partial seizures and  is a drug of choice for initial therapy, particularly in treating adults

Mechanism of action

Phenytoin blocks voltage-gated sodium channels by selectively binding to the channel in the inactive state and stabilizes the neuronal membrane

It inhibits the generation of repetitive action potentials

At much higher concentrations , phenytoin can block voltage-dependent calcium channels and  interfere with the release of monoaminergic neurotransmitters

Pharmacological action

Phenytoin exerts antiseizure activity without causing general depression of the CNS

It is one of the most effective drugs against generalized tonic-clonic seizures and partial seizures

Phenytoin reduces the propagation of abnormal impulses in the brain

Pharmacokinetics

Phenytoin is poorly water soluble  hence absorption is slow

It is 90% bound to plasma proteins

It is metabolized in liver

Phenytoin is enzyme inducer

Therapeutic uses

Phenytoin is highly effective for all partial seizures ( simple and complex), for tonic-chronic seizures and in the treatment of status epileptics

Phenytoin is not effective for absence seizures, which often may worsen if treated with this drug

Adverse effects

It depend dose , duration and route

Nausea, vomiting, epigasric pain, anorexia

Nystagmus, diplopia, ataxia are common

Gingival hyperplasia is more common in children on prolonged use

Peripheral neuropathy

Phenytoin inhibits insulin release and produces hyperglycemia

Decreases the release of ADH

Osteomalacia , hypocalcaemia due to altered metabolism of vitamin D and inhibition of intestinal absorption of Ca

Hypersensitivity  - Rashes , SLE, hepatic necrosis , and neutropenia

Megaloblastic anemia – Phenytoin decreases absorption and increases excretion of folates

Teratogenicity

When taken by the pregnant lady, phenytion produces foetal hydantion syndrome characterized by hypo plastic phalanges, cleft palate,  and harelip

Drug interactions

Phenytoin is an enzyme inducer

Phenytoin given with phenobarbitone , both increases  each other metabolism

Phenytoin and carbamazepine enhance each others metabolism

Valproate displaces protein bound phenytoin

Cimetidine and chloramphenicol  inhibit the metabolism of phenytioin  resulting in toxicity

Antacids decreases the absorption of phenytoin

Phenobarbitone

Phenobartitone was the first effective antiepileptic drug to be introduced in 1912. It still remains one of the widely used drugs

It has antiepileptic activity and raises the seizure threshold

Mechanism of action

Barbiturates enhances the inhibitory neurotransmission in the CNS by enhancing the activation of GABA receptors and facilitating the GABA mediated  opening of chloride ion channels

Pharmacokinetics

It is well absorbed orally

The drug freely penetrates  the brain

Approximately 75 % of the drug is inactivated by the hepatic mocrosomal system, whereas the examining drug is excreted unchanged by the kidney

It is a potent inducer of the cytochrome P450 system and when given chronically, it enhances the metabolism of their agents

Therapeutic uses

It provides favorable response for simple partial seizures, but it is not very effective for complex partial seizures

The drug had been regarded as the first choice in treating recurrent seizures in children, including febrile seizures

It also used to treat recurrent tonic-clonic seizures, especially in patients who donot respond to diazepam plus phenytoin

It also used as  a mild sedative to relieve anxiety, nervous tension and insomnia

Adverse effects

Sedation, ataxia, vertigo , nausea and vomiting

Agitation and confusion occur  at high doses

 

Rebound seizures can occur on discontinuance of Phenobarbital

Primdone

It structurally related to Phenobarbital and it resembles Phenobarbital in its anticonvulsant activity

It is an  alternative choice in partial seizures and tonic – clonic seizures

It has more efficacy due to the its metabolites Phenobarbital and phenyl-ethyl-malonamide which have longer half- lives than the parent drug

It is effective against tonic-clinic and simple partial seizures and phenyl-ethy-lmalonamide is effective against complex partial seizures

Primidone is often used with carbamazepine and phenytoin

It is well absorbed orally

It exhibits poor protein binding

These drug has the same adverse effects as those seen with Phenobarbital

 

Benzodiazepines

Several of the benzodiazepines show antiepileptic activity

Diazepam and lorazepam are the drugs of choice in the acute treatment  whereas Clonazepam and clorazepate and clorazepate are used for chronic treatment of status epilepticus

Clonazepam

It suppresses seizure spread from the epileptogenic focus and is effective in absence and myoclonic seizures , but tolerance develops

Clonazepate

Clorazepate is effective in partitial seizures when used in conjunction with other drugs

Diazepam

It is effective against

Petitmal epilepsy

Mylclonic seizures

Status epilepsy

It is drug of choice for status epilepticus

Lorazepam

 Lorazepam and diazepam  are both effective in interrupting the repetitive seizures of status epilepticus.

Lorazepam has a longer duration of action and is preferred by some clinicians

All of the antiepileptics, the benzodiazepines are the safest and most free from severe side effects

All benzodiazepines have sedative properties

Side effects

Drowsiness,

Somnolence,

Fatigue,

Ataxia,

Dizziness and behavioral changes

Respiratory depression and cardiac depression may occur when given intravenously in acute situations

Ethosuximide

It reduces propagation of abnormal electrical activity in the brain, most likely by inhibiting t- type calcium channels in a manner similar to the action of phenytoin on sodium channels

It is the first choice in absence seizures

It is well absorbed orally and is not bound to plasma proteins

About 25% of the drug is excreted unchanged in the urine and 75% is converted to inactive metabolites in the liver by the microsomal cytochrome P450 system

It does not induce P450 enzyme synthesis

The drug is irritating to the stomach and nausea and vomiting may occur on chronic  administration

Drowsiness, lethargy, dizziness , restlessness , agitation , anxiety and the inability to concentrate are often observed

Valproic Acid

It is a broad spectrum anticonvulsant

It has multiple actions , including sodium channel blockade and enhancement of GABAergic transmission

It is the most effective agent available for treatment of myoclinec seizures

It also diminishes absence seizures, but because of its hepatotixic potential, it is a second choice

It also reduces the incidence and severity of tonic-clonic  seizures

The drug is effective orally and is rapidly absorbed

About 90% is bound to the plasma proteins ,only 3%  of the drug is excreted unchanged, the rest is converted into active metabolites by the liver

It is metabolized by cytochrome P450 enzymes

Metabolites are excreted by kidney

It can cause nausea, vomiting ,sedation, ataxia and tremor are common

It inhibits the metabolism of a number of antiepileptic drugs , including Phenobarbital, carbamazepine and ethosuximide

Carbamaepines

Actions

It reduces the propagation of abnormal impulses in the brain by blocking sodium channels, thereby inhibiting the generation of repetitive action potential in the epileptic focus and preventing their spread

ADME

It is absorbed slowly following oral administration

It enters the brain rapidly because of its high lipid solubility

It induces the drug metabolizing enzymes in the liver

The enhanced hepatic cytochrome p450 system activity also increases the metabolism of many drugs including other antiepileptic drugs

It is an inducer of the cytochromep450  isozyme  cyp3a4, which decrease                                                      the effects of drugs that are metabolized by his enzyme

Therapeutic uses

It is effective in Temporal lobe epilepsy

Trigeminal neuralgia

Used in post hepatic pain

Adverse effects

Chronic administration of carbamazepine can cause stupor, coma and respiratory depression

It also produces drowsiness, vertigo, ataxia, and blurred vision

The drug is irritating to the stomach and nausea and vomiting may occur

Drug interaction

The hepatic metabolism of carbamazepine is inhibited by several drugs

Toxic symptoms may arise if the dose is not adjusted

Pharmacy

It is art and science of compounding and dispensing of drugs  or preparing suitable dosage forms for administration of drugs to man or animals

It includes collection, identification, purification, isolation, synthesis, standardization and quality control of medicinal substances

The large scale manufacture of drugs called pharmaceutics

Pharmacology

It is a  Greek  word .    Pharmacon -----  Drug .       Logos----- discourse in

Drug

French   ---  Drogue  -----   a dry herb

It is single active chemical entity present in medicine that is used for diagnosis, prevention, treatment or cure of disease

Drug nomenclature

1. Chemical name
2. Generic name   ( Non- Proprietary name)
3.  Brand name     ( Proprietary name )

Sources of drugs

Drugs are obtained from different sources

Most of the drugs that are currently used are manufactured synthetically

Recently drugs are synthesized by genetic technologies  like human recombinant gene technology

Ex 

Erythropoietin

Source	Specific source and drugs	Category
Plants	Belladonna- Atropine Digitalis- Digitoxin Opium - Morphine	Ant cholinergic Cardio tonic Narcotic analgesics
Animals	Pork, Beef – Insulin Horse – Tetanus anti toxin Various animals - Heparin	Anti-diabetic Ant tetanus Anti- coagulant
Minerals	Charcoal Magnesium sulfate Aluminum hydroxide	Antidote Purgative Antacid
Microbes	Penicillium Notatum – Penicillin Actinomycetes – Streptomycin E. Coli  - L- asparaginase	Antibiotic Antibiotic Anti-cancer
Synthetic	Aspirin Cimetidine Paracetamol Phenitoin Phenobarbitone	Analgesics Antacid Anti-pyretic Anti-epileptic Hypnotic

Dosage forms

Pharmaceutical companies dispense a drug in a variety of formulations suitable for a single or multiple routes of administration

Some antibiotics are available in tablet, capsules or suspension form for oral administration

So doctor can choose the formulation suitable for the patient

It is important because it influences the bioavailability of drug

For ex

Digoxin when injected intravenously, the bioavailability of that drug is 1.00

But when the same amount of the drug is administered into the body by oral route in tablet form, the bioavailability is about is 0.62

On the other hand, the bioavailability of digoxin elixir administered orally  is 0.80

When a tablet form of drug is swallowed, it is necessary to disintegrate as well as to dissolve before absorption

But in case of capsule, there is no question of disintegration , only dissolution is necessary

In case of suspension, there is no disintegration or dissolution

So, the rate of absorption is greater in suspension than capsule or tablet

Route of administration

To produce a pharmacological effect it is very important for the drug to reach the site of action

This depends on the transfer of drugs across one or more membrane barriers

Drugs after reaching the blood circulation  builds up a therapeutic concentration

The concentration depends on the volume of distribution, biotransformation and excretion

There are some drugs which are not absorbable from one site but get into the circulation from another

Benzyl penicillin is inactivated in the stomach at gastric PH and is not administered orally

Some drugs absorbed from the gastrointestinal tract  pass the intestinal mucosa and  the small  intestine but metabolized  by the gut  wall (such as chlorpromazine , dopamine) or

by  the liver ( such as lignocaine, pethidine, propranolol)

In order to select the route for administration this first-pass biotransformation is considered and on occasions is avoided

Slowly absorbed drug may have delayed onset of effect and may even fail to achieve effective concentration

Route of administration

To produce a pharmacological effect it is very important for the drug to reach the site of action

This depends on the transfer of drugs across one or more membrane barriers

Drugs after reaching the blood circulation  builds up a therapeutic concentration

The concentration depends on the volume of distribution, biotransformation and excretion

There are some drugs which are not absorbable from one site but get into the circulation from another

Benzyl penicillin is inactivated in the stomach at gastric PH and is not administered orally

Some drugs absorbed from the gastrointestinal tract  pass the intestinal mucosa and  the small  intestine but metabolized  by the gut  wall (such as chlorpromazine , dopamine) or

by  the liver ( such as lignocaine, pethidine, propranolol)

In order to select the route for administration this first-pass biotransformation is considered and on occasions is avoided

Slowly absorbed drug may have delayed onset of effect and may even fail to achieve effective concentration

Alcohols

Alcohols are aliphatic hydrocarbons

They contain one or more hydroxyl groups

Classification

1. Mono-hydroxy alcohols

Methyl, ethyl and propyl alcohols

2. Dihydroxy alcohols

Ethylene glycols, propylene glycol

3. Tri-hydroxy alcohols

Glycerol or glycerine

4. Poly-hydroxy alcohols

Mannitol,  sorbitol

Ethyl alcohol

Ethyl alcohol is commonly used alcohol

It is the main constituent of all kinds of alcoholic beverages

It is generally obtained by fermentation of sugars by yeast

The alcohol is separated by simple distillation

It is a colorless, volatile and inflammable liquid

The alcohol content of various beverages varies between 4-55% by volume

Wines containing more than 16%  of alcohol

Beer contains 4-6 % (v/v) of alcohol

Stronger preparation are called Spirit

Mechanism of action

Alcohol produce CNS depression by a generalized membrane action by altering the state of membrane lipids

Alcohol promotes GABA_A receptor mediated synaptic inhibition (through chloride channel opening ) as well as inhibits NMDA and type of excitatory amino acid receptors (operating thorough captions channels)

Alcohol can indirectly reduce neurotransmitter release by inhibiting voltage sensitive neuronal calcium channels

Blockade of adenosine uptake by alcohol could also contribute to synaptic depression

The activity of membrane bound enzymes like Na – K ATPase and adenyl cyclase is also altered

The activity and translocation of channel or enzyme proteins in the membrane could be affected by alcohol through protein kinase  C and protein kinase A mediated alteration in the state of their phosphorlation

Pharmacological actions

1. Externally

It evaporates quickly and producing cooling effect and is used for reducing the temperature in fevers

It is used in shaving lotion for producing cooling effect on the skin

In  concentration of  40- 50,  it act as rubifacient and mild irritant action

In concentration of 70% , it acts as antiseptic , the action is seen only against vegetative forms of organism and spores are resistant

Concentrated alcohol , if injected , produces tissue destruction

Higher concentration  denature proteins by partial precipitation and dehydration

In such concentration , it acts as an astringent, a germicidal and an irritant

  

2. GIT

If  taken orally , it increases salivary secretion by reflex action

It has an irritant action on the gastric mucous membrane and act as appetizer

50 ml of 7-10% alcohol increases the gastric secretion ,by releasing histamine and gasstrin  from the antrum of the stomach

Concentration  above 15%  inhibit both motility and secretion and effect may persist for many hours

Concentration above 20% reduce the enzymatic activity of the gastric and the intestinal juices

Concentration above 40% and over have a direct toxic effect on gastric mucosa and may precipitate gastritis, giving rise to pain, nausea, vomiting and other symptoms

Many alcoholics suffer from gastritis and chronic achlorhydria

Many alcoholics suffer from chronic diarrhea as a result of malabsorption from chronic mucosal damage

3. CNS

It is primarily a CNS depressant and acts by enhancing the inhibitory GABA receptor activity or inhibiting NMDA receptors

Proteins are the  primary site of its actions

It  produces initial excitation due to depression of higher inhibitory centers

This is followed by progressive depression, drowsiness, sleep and unconsciousness as the dose is increased

Sudden withdrawal of alcohol causes excitation and hyperactivity of the CNS

4. CVS

Small dose produce only cutaneous and gastric vasodilatation B.P is not affected

Moderate doses cause tachycardia and a mild rise in BP due to increased muscular activity and sympathetic stimulation

Large doses cause direct myocardial as well as  vasomotor centre depression and there is fall in BP

Chronic alcoholism may contribute to hypertension and lead to cardiomyopathy

Atrial fibrillation and other cardiac arrhythmias may occur due to conduction defects and Q-T  prolongation

5. On respiration

Moderate doses produce slight stimulation whereas large doses produce respiratory depression which may be fatal

6. Kidney

Diuresis is often notified after alcohol intake

It is due to depression of ADH production

It does not impair renal function

7. Sax

Alcohol is reputed as an aphrodisiac.

Aggressive sexual behavior is due to loss of inhibitory control

It also provokes the sensation but takes away the performance

Chronic alcoholism can produce impotence, gynaecomastia and infertility

8. Body temperature

Alcohol  produces  a sense of warmth due to cutaneous and gastric vasodilatation , but heat loss is increased in cold surroundings   

High intake of alcohol produces depress temperature regulating centre

9. Liver

It produces fatty liver on chronic administration

It mobilize peripheral fat and increases fat synthesis in liver

Proteins may also accumulate in liver because their secretion is decreased

Acetaldehyde produced during metabolism of alcohol appears to damage the hepatocytes on chronic ingestion of large amounts

Increased lipid peroxidation and glutathione depletion occurs

Regular alcohol intake induces microtonal enzymes

10. Skeletal muscle

Alcohol produces little direct effect.  Fatigue is produced by small doses, but muscle work is increases or decreased

Weakness and myopathy occurs in chronic alcoholism

11. Blood

Regular intake of small to moderate amounts has been found to raise HDL levels and decrease LDL oxidation

 Megaloblastic anemia has been seen in chronic alcoholism due to interference with folate metabolism

Absorption , fate and excretion

Alcohol is absorbed in the stomach (25%) and 75% in small intestine

It is metabolized in the liver as follows

                            Alcohol dehydrogenase

Ethyl alcohol   -------------------------------------------------------Acetaldehyde

                             Aldehyde dehydrogenase

Acetaldehyde-------------------------------------------------------------Acetyl CoA

Acetyl CoA is further metabolized to carbon dioxide and water

Alcohol is eliminated mostly through kidneys and lungs

Toxicity

Side effects of moderate drinking

Nausea, vomiting , flushing, hangover, traffic accidents

Acute alcoholic intoxication

Fall in body temperature

Hypotension

gastritis

hypoglycemia

Collapse, respiratory depression

Coma  and death

Treatment

Gastric lavage maintain patent airway and take steps to prevent aspiration of vomit us

Positive pressure respiration may be needed if it is markedly depressed

Most patients  will recover with supportive treatment, maintenance of fluid and electrolyte balance and correction of hypoglycemia  by glucose infusion  till alcohol is metabolized

Recovery can be hastened by haemodialysis

Insulin + fructose drip has been found to accelerate alcohol metabolism

Chronic alcoholism

On chronic intake, tolerance develops to subjective and behavioral effects of alcohol

It is both pharmacokinetic and cellular tolerance

Psychic dependence often occurs even with moderate drinking

Physical dependence occurs only on heavy and round the clock drinking

Heavy drinking is often associated with nutritional deficiencies, because food is neglected and malabsorption  may occur

Alcoholic cirrhosis of liver, hypertension, cardiomyopathy , CHF, arrhythmias, stroke and skeletal myopathy are complications

Treatment

Psychological and medical supportive measures are needed during withdrawal

Many CNS depressants like barbiturates , phenothiazines, chloral hydrate have been used as substitution therapy in the past to suppress withdrawal syndrome but benzodiazepines like chordiazepoxide, diazepam are the  preferred drugs now

These have a long duration of action and can be gradually withdrawn later

Disulfiram

It is a drug for the treatment of chronic alcoholism

It is a inhibits the enzyme aldehyde dehydrogenaase

So acetaldehyde is not converted into Acetyl CoA

This leads to accumulation of acetaldehyde which  produces nausea and vomiting

It is administered at a dose of 500 mg once daily for a week and alter 250 mg daily as maintenance dose

When alcohol is ingested after taking disulfiram, the concentration of acetaldehyde in tissues and blood rises and a number of distressing symptoms (aldehyde syndrome ) are produced

These are

Flushing 

Burning sensation

Throbbing headache

Perspiration

Uneasiness

Tightness in chest 

Dizziness

Vomiting

Visual disturbances

Mental confusion and circulatory collapse

Duration  of the syndrome (1-4 hours ) depends on the amount of alcohol consumed

Disulfiram is used in chronic alcoholics who are motivated and sincerely desire to leave the habit

Sensitization to alcohol develops after 2-3 hours of first dose and lasts for 7-14 days after stopping it ,because  inhibition of aldehyde dehydrogenase with disulfiram is irreversible

Synthesis of fresh enzyme is required for return  of activity

It should not be used in patients who are physically dependent on alcohol

Side effect of disulfiram are

Drowsiness

Headache

Cramps

Rashes

Metallic taste

Nervousness

Abdominal upset

General anesthetics

Def

General anesthetics are drugs which produce reversible loss of all sensation and consciousness

Conditional feature of General anesthetics are

Loss of all sensation. Specially pain

Sleep ( unconsciousness) and amnesia

Immobility and muscle relaxation

Abolition of reflexes

1. Inhalation anesthetics

A. Gas

Nitrous oxide

Cyclopropane

Ethylene

B. Liquids

Ether

Chloroform

Halothane

Ethyl chloride

Vinyl ether

11. Intravenous anesthetics

Thiopentone

Methohexitone

Ketamine

Paraldehyde

 

Ether ( Di-ethyl ether )

Properties

It is one of the oldest anesthetic agents in use

It is a colorless and volatile liquid with a pungent odour

It is highly inflammable and explosive

It is quickly absorbed and eliminated through lungs

Actions

5-10% of ether is required in the inspired air to induce anesthetic and at least 3-5% to maintain it

It irritates respiratory tract leading to eflex secretion of saliva and mucous from the mouth and respiratory tract

So atropine should be given at least half an hour before to paralyses secretion

The initial stages are more prolonged with ether in the absence of premeditation

Other actions

Ether does little damage to the heart

It increases cardiac output and coronary blood flow

The rate and depth of respiration may be increased

It does not cause any damage to liver

Advantages

It is safest agent . It can be used even by a nurse

It produces analgesia

It produces skeletal muscle relaxation

It produces less inhibition of respiratory centre than other unaesthetic agents   

It does not effect the blood pressure

It dies not interfere with liver or kidney functions

It can be given by all techniques

Dis-advantages

It catches fire

Induction of anesthesia as well as Recovery are slow

Vomiting is likely to occur postoperatively

Generalized convulsions are produced specially in children

  

Chloroform

It is a volatile liquid having a powerful anesthetic property

It is a colorless non-inflammable volatile liquid with a sweetish smell

It produces server toxic effects on the liver and heart

It is not used at present

Action

Anesthesia is induced by the open drop method or by closed circuit method 2%  of chloroform is required in the inspired air to induce anesthesia and about 0.5% for maintenance of anesthesia

Other action

In addition to general an aesthesia, externally it is used as a rubefacint

Internally it is used as a carminative

It is used as a vehicle in mixtures

Advantages

It does not irritate respiratory tract

Muscular relaxation is good

Recovery is accompanied by less nausea and vomiting than with ether

It is non inflammable

Induction is rapid and pleasant

Disadvantages

Chloroform depresses myocardium resulting in slowing down of the heart and even cardiac arrest

It depresses the respiratory centre

Liver function is affected leading to necrosis and hepatic failure and death

Intestinal motility is diminished

Margin of safety is very less

Blood concentration of about 15 mg% is required to maintain anesthesia but about 20-25 mg% is fatal

 

Halothane

Physical properties

It is heavy, colorless liquid, anesthetic agent

It is non inflammable, non toxic fluorinated hydrocarbon

It has sweet , fruity odor and boils

It affects most of metals including stainless steel ,,copper, rubber

Advantages

Induction is very smooth as it has sweet , fruity odor

Recovery is also fast , smooth with low incidences of nausea and vomiting It is not inflammable and hence does not irritate respiratory passage inhibits salivary secretion hence endotracheal intunotion is much easier

It does not produce bronchospasm, and can be used in patients with bronchial asthma

Dis advantages

Muscular relaxation is inadequate

It causes respiratory, cardiovascular depression

Mental recovery is delayed

Shivering during recovery is very common

It is poor analgesic

It is expensive, needs special apparatus for administration